tbuckley/cabot-search huggingface dataset:
BIOL-24. USING NEEDLE WASH SPECIMEN AFTER STEREOTACTIC BIOPSY TO DEVELOP PDOX MODELS OF DIPG AND DIFFUSE MIDLINE GLIOMAS
Authors: Aalaa Abdallah, Michael DuCuypere, Sophie Xiao, Milagros Suarez, Nitin Wadhwani, Yuchen Du, Sandi Lam, Xiao-Nan Li
Journal: Neuro-Oncology (2023)

Abstract Obtaining viable tissue remains a major barrier for lab-based studies, especially in brain tumors deemed surgically unresectable such as diffuse midline gliomas. Surgical biopsy is performed for those tumors invested in deep and vital brain structures however, biopsied specimens are usually of small volume without additional tissue for research after clinical testing. To overcome the barrier of limited surgical specimen volume, we partnered with neurosurgeons to develop a protocol which procures viable cells from discarded biopsy needle after stereotactic biopsies to develop patient-derived orthotopic xenograft (PDOX) models. After procurement of surgical specimen and prior to disposal of biopsy needle, each stereotactic biopsy needle was washed with FBS media twice. Wash solution was collected and immediately transported on ice to the research lab. Cell number was counted for in vitro culture and for orthotropic in vivo tumor implantation. To date, 29 samples of biopsy needle washes have been obtained including 12 diffuse midline gliomas of the brain stem, 8 supratentorial diffuse midline gliomas, and 3 pineal region tumors with harvested cell number from no visible cells to 5.3 million cells (median 1 million). 14 tumors have been orthotopically implanted into matched locations of immunodeficient mouse brains. Tumor formation was confirmed in 4 out of 15 (28.5%), including 2 brain stem tumors, 1 infiltrating astrocytoma, and 1 midline glioma, after implantation of cell numbers as low as 12,500. 3 models were successfully sub-transplanted to passages II and III. Histological examination confirmed the replication of key pathological features of the originating patient tumors. In conclusion, we have developed a novel protocol to procure clinical specimen by using wash solution of stereotactic brain tumor biopsy needles for surgically unresectable tumors. Our work demonstrates a new possibility for clinical sample acquisition and tumor modeling, opening new frontiers in the field of pediatric brain tumor research.
A very rare case of extraskeletal Ewing sarcoma of the duodenum presenting as gastrointestinal hemorrhage
Authors: Zilong Zhang, Xin He, Songqi Wen, Xin Jin, Ding Xiao, Jian You
Journal: Endoscopy (2023)

A 51-year-old man presented to our hospital with hematochezia, melena, palpitations, and lightheadedness for 1 week. The patient was found to have anemia with a hemoglobin concentration of 73 g/L and a peripheral blood smear suggestive of hypochromic microcytic anemia. To confirm upper gastrointestinal bleeding, an esophagogastroduodenoscopy was performed, revealing a protruding lesion with surface ulceration and active bleeding at the inferior flexure of the duodenum ([Fig. 1 a]). The lesion was located on top of a submucosal elevation of approximately 3 × 2.5 cm in size ([Fig. 1 b, c]). He received endoscopic hemostasis, including epinephrine injection, argon plasma coagulation, and hemoclipping ([Fig. 1 d], [Video 1]). The biopsy was suggestive of small cell carcinoma. To obtain more details for the optimal surgical approach, abdominal computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP) showed a target-like lesion with eccentric wall thickening at the inferior flexure of the duodenum, measuring approximately 2.8 × 2.4 cm in diameter ([Fig. 2 a–c]).
TRLS-14. TARGETING REPLICATIVE STRESS IN BRAIN TUMORS BY COMBINING ATR AND PARP INHIBITION
Authors: Supriya Sarvode, Alaa Refaat, Rebekah DeVries, Anasuya Pal, Christopher Tinkle, Anang Shelat
Journal: Neuro-Oncology (2023)

Abstract Pediatric brain tumors like MYC-amplified Medulloblastomas (MB) and Atypical Teratoid and Rhabdoid Tumors (AT/RT) continue to have poor survival rates despite recent advances in understanding tumor biology. MYC is an oncogenic transcription factor often expressed in MB and AT/RT at high levels. While direct inhibition of MYC by small molecules is an active area of research, such approaches lack clinical validation and are not yet actionable. Strategies to target MYC-driven brain tumors that are immediately translatable are urgently needed. Replication stress has been identified as a prominent source of tumorigenesis over the past decade and is a potential target for cancer therapy. Specific oncogenes induce elevated levels of replicative stress through aberrant activation of transcription and dysregulation of DNA replication. In these instances, replicative stress could be rescued by either metabolic supplementation or MYC expression. The activation of ATR and PARP are critical events in response to replicative stress. PARP inhibitors stall replication forks and promote the generation of single-strand DNA, which activates ATR. Genetic and pharmacological evidence suggests the sensitization of MYC-induced tumors to PARP inhibitors. Preclinical studies in diverse tumor backgrounds have demonstrated that the combination of ATR and PARP inhibition is synergistic and leads to premature entry into mitosis, enhanced replicative stress and cell death, and tumor regression. Additionally, a reduction in ATR activity can be lethal in oncogene-induced replication stress. Using high throughput drug screening across MB and AT/RT cell lines, we found that the CNS penetrant PARP inhibitor AZD9754 significantly potentiated the cytotoxicity of ATR inhibition. This emerging synergistic combination therapy reveals new therapeutic targets in MYC-driven replicative stress. Studies are ongoing to validate in vitro findings in vivo.
MDB-05. HUMAN FETAL CEREBELLAR CELL ATLAS INFORMS MEDULLOBLASTOMA ORIGIN AND ONCOGENESIS
Authors: Zaili Luo, Richard Lu
Journal: Neuro-Oncology (2023)

Abstract Medulloblastoma (MB) is the most common malignant childhood brain tumor, yet the origin of the most aggressive subgroup-3 form remains elusive, impeding development of effective targeted treatments. Previous analyses of mouse cerebella or human counterparts from frozen tissue nuclei5 have not fully defined the compositional heterogeneity of MBs. Here, we undertook an unprecedented single-cell profiling of freshly-isolated human fetal cerebella to establish a reference map delineating hierarchical cellular states in MBs. We identified a unique transitional cerebellar progenitor connecting neural stem cells to neuronal lineages in developing fetal cerebella. Intersectional analysis revealed that the transitional progenitors were enriched in aggressive MB subgroups, including group-3 and metastatic tumors. Single-cell multi-omics revealed underlying regulatory networks in the transitional progenitor populations, including transcriptional determinants HNRNPH1 and SOX11, which are correlated with clinical prognosis in group-3 MBs. Genomic and Hi-C profiling identified de novo long-range chromatin-loops juxtaposing HNRNPH1/SOX11-targeted super-enhancers to cis-regulatory elements of MYC, an oncogenic driver for group-3 MBs. Targeting the transitional progenitor regulators inhibited MYC expression and MYC-driven group-3 MB growth. Our integrated single-cell atlases of human fetal cerebella and MBs reveal potential cell populations predisposed to transformation and regulatory circuitries underlying tumor cell states and oncogenesis, highlighting hitherto unrecognized transitional progenitor intermediates predictive of disease prognosis and potential therapeutic vulnerabilities.
Endoscopic treatment of a post-surgical dehiscence of an esophageal–ileal–colonic reconstruction: when endoscopy reaches its limit
Authors: Giacomo Emanuele Maria Rizzo, Lucio Carrozza, Salvatore Tammaro, Dario Ligresti, Ilaria Tarantino, Mario Traina
Journal: Endoscopy (2023)

A 55-year-old man was referred to our institute after total gastrectomy and partial esophagectomy for a gastroesophageal tumor. Esophageal reconstruction included the right colon and the last loop of the ileum with esophageal–ileal, colonic–jejunal, and jejuno–jejunal anastomoses (Roux-en-Y reconstruction). Following the initial surgery, a computed tomography scan showed a suspected anastomotic leak with the development of intrathoracic/intra-abdominal collections, so the patient underwent a second surgical procedure with placement of a thoracic/abdominal drain.
OUTC-12. BLACK IN CANCER: EMPOWERING AND ENCOURAGING FUTURE BLACK CANCER LEADERS WHILST REDUCING CANCER DISPARITIES THROUGH EDUCATION AND ADVOCACY
Authors: Sigourney Bonner
Journal: Neuro-Oncology (2023)

Abstract From its inception in 2020, Black in Cancer has been modelling an action-oriented approach to improving representation across the cancer community. Black in Cancer (BIC) was founded during the racial justice protests that swept across the globe in the midst of a number of Black professionals aiming to promote visibility and sharing of resources within their respective groups leading to “Black in X” communities on social media and in particular twitter. This network was required in the cancer community with Black cancer researchers, clinicians and patient advocates being underrepresented and Black patients underserved. Black or African American workers make up 12% of the U.S. working population but represent just 9% of STEM workers. Dissected even further, only 3% of medical oncologists are Black and training programs such as oncology fellowships have minimally increased between 2006 and 2018. For researchers, this disparity is even more prominent, as only 1% of all professors in biology at U.S.institutions are Black and just 0.6% in the UK. Studies show that Black researchers are about 55% less likely to receive NIH funding than white researchers. Several studies from AACR and Cancer Research UK show that Black patients are diagnosed at a later stage, with more aggressive cancers and have a higher mortality rate. Our organisation has two main initiatives to tackle these challenges, through our Cancer Awareness Project (CAP)and the Mentorship and Outreach Program (MOP). These programmes have delivered $2 million in funding for Black cancer researchers at the postdoctoral level and above, and have also supported almost 40 undergraduate students through our mentorship program. Our CAP initiative has delivered a number of informational sessions to the community in how to identify symptoms, diagnosis pathways and how patients can be informed and empowered about their healthcare decisions.
DIPG-43. CLINICAL AND MOLECULAR CHARACTERISTIC OF A NEW SUBTYPE OF DMG, H3K27-ALTERED WITH MAPK-ACTIVATING CO-DRIVER MUTATIONS
Authors: Lucie Auffret, Yassine Ajlil, Thomas Kergrohen, Arnault Tauziède-Espariat, Chloé Puiseux, Laurent Riffaud, Alberto Picca, Medhi Touat, Marc Sanson, Kevin Beccaria, Thomas Blauwblomme, Volodia Dangouloff-Ros, Nathalie Boddaert, Pacale Varlet, Marie-Anne Debily, Jacques Grill, David Castel
Journal: Neuro-Oncology (2023)

Abstract Diffuse midline gliomas (DMG) represent a big challenge in neuro-oncology. These tumors occur more frequently in children and are presently incurable. They are characterized by a K27M substitution in H3.1 or H3.3 histone tail or the overexpression of EZHIP (EZH Inhibitory Protein). These three alterations induce a global loss of trimethylation in H3K27 with a specific epigenic and transcriptomic remodeling. The additional oncogenic events and the clinical behavior are also distinct according to the driver event. Based on these differences, the H3K27-altered DMG is now classified in 4 subtypes by the latest edition of the WHO Classification of CNS tumors. Even with this new subclassification, the H3.3K27M subgroup still appears heterogenous. Recent publications reported that rare patients presenting a co-occurrence of H3.3K27M with BRAF or FGFR1 alterations tend to have a better prognosis. To better study the role of these co-driver alterations that activate the mitogen activated protein kinase (MAPK) signaling, we assembled a large pediatric and adult cohort of H3K27-altered DMG comprising 25 new DMG patients mutated in FGFR1 or BRAFV600E and 37 previous cases from the literature. We performed a comprehensive histological, radiological, genomic, transcriptomic and DNA methylome analysis on this extended cohort. Interestingly, the results show clear differences with other DMG subtypes, including: specific DNA methylation profile, senescence signature, better overall survival (median around 3 years), older age at diagnosis, specific histological and radiological presentations with calcifications or more circumscribed tumors. Additionally, in specific cases, we show that the MAPK-activating mutation occurred subsequently to the histone H3K27M mutation. In conclusion, DMG, H3K27-altered harboring MAPK activating mutations represent a new subtype of DMG also frequent in adults, and deserve further attention with respect to specific therapeutic challenges.
DIPG-18. AI HUNTING FOR NEW DRUGS IN PEDIATRIC GLIOMA
Authors: Rintaro Hashizume, Patrick Newbury, Yukitomo Ishi, Guisheng Zao, Benjamin Glicksberg, Shreya Paithankar, Javad Nazarian, Michael Pacold, Jun Watanabe, Eita Uchida, Theodore Nicolaides, Bin Chen
Journal: Neuro-Oncology (2023)

Abstract Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating pediatric gliomas, with nearly all patients succumbing to progressive tumor growth within two years of diagnosis. The identification of effective therapeutics based on the genetic features is of high importance for improving treatment outcomes for DIPG patients. We have developed machine learning algorithms that allow profiling thousands of genetic features, which can all contribute towards drug discovery. This study aimed to identify potential therapeutic agents using a computational pipeline to perform an in-silico screen for novel drugs. We then tested the identified drugs against a panel of patient-derived DIPG cell lines. Using a systematic computational approach with publicly available databases of gene signature in DIPG patients and cancer cell lines treated with a library of clinically available drugs, we identified drug hits with the ability to reverse a DIPG gene signature to one that matches normal tissue background. The biological and molecular effects of drug treatment was analyzed by cell viability assay and RNA sequence. In vivo DIPG mouse model survival studies were also conducted. As a result, two of three identified drugs showed potency against the DIPG cell lines. Triptolide and mycophenolate mofetil (MMF) demonstrated significant inhibition of cell viability in DIPG cell lines. Guanosine rescued reduced cell viability induced by MMF. In vivo, MMF treatment significantly inhibited tumor growth in orthotopic DIPG xenograft models. In conclusion, we identified clinically available drugs with the ability to reverse DIPG gene signatures and anti-DIPG activity in vitro and in vivo. This novel approach can repurpose drugs and significantly decrease the cost and time normally required in drug discovery.
Needle in a haystack: an unusual case of video capsule endoscope retention
Authors: Jiayinaer Bolatihan, Lingxi Lin, Yujen Tseng, Pinghong Zhou, Lili Ma
Journal: Endoscopy (2023)

A patient was admitted with a 1-month history of intermittent abdominal pain, often associated with pre-prandial exacerbation. Then, 2 days prior to admission, the patient experienced hematochezia, with a rapid decline in hemoglobin level from 131 g/L to 80 g/L to 61 g/L. The patient underwent gastroscopy and colonoscopy, but no obvious cause of gastrointestinal bleeding was found.
IMG-06. RADIOMIC-BASED RISK STRATIFICATION OF PEDIATRIC LOW-GRADE GLIOMA REVEALS DIFFERENTIALLY EXPRESSED MOLECULAR PROCESSES CONTRIBUTING TO VARIABLE PATIENT PROGNOSIS
Authors: Anahita Fathi Kazerooni, Meen Chul Kim, Adam Kraya, Aria Mahtabfar, Debanjan Haldar, Komal Rathi, Nastaran Khalili, Ariana Familiar, Jeffrey B Ware, Sina Bagheri, Hannah Anderson, Phillip B Storm, Adam C Resnick, Arastoo Vossough, Christos Davatzikos, Ali Nabavizadeh
Journal: Neuro-Oncology (2023)

Abstract In pediatric low-grade gliomas (pLGG), prognosis and responses to treatments are heterogeneous. This heterogeneity may be explained by the differences in molecular composition of the tumors of the same histology and the likely upstream alterations following administered radiation or systemic therapy. Integration of radiomics and clinical variables could generate a non-invasive biomarker that provides upfront prediction about patient’s risk of progression. We show that our proposed radiomic-based risk-stratification signature for pLGGs is associated with alterations in transcriptomic pathways. Standard multiparametric MRI sequences of 134 pLGG patients from Children’s Brain Tumor Network (CBTN) were retrospectively collected and 881 quantitative radiomic features were extracted. A multivariate Cox proportional hazard’s (Cox-PH) regression model was fitted on clinical (age, sex, tumor location, and extent of tumor resection) along with radiomic variables using 5-fold cross-validation, to predict patient’s risk of progression. The Cox-PH model showed excellent performance in prediction of PFS and patient’s risk scores, supported by the concordance index of 0.78. Radiogenomic analysis was performed to determine the transcriptomic pathways (1594 pathways, c2 MsigDb Reactome v2022.1) that contribute to the pLGG risk, predicted by the radiomic signature. ElasticNet regression was applied on the scores obtained by gene set enrichment analysis (GSEA) (in 70/134 subjects) to predict radiomic-based risk scores. Increased risk, corresponded to upregulation of DNA repair pathways, dysregulation of lipophagy, fatty acid beta oxidation, and vitamin D pathways, which are tumor-promoting. BRAFfusion signaling inversely correlated with risk, consistent with known favorable prognosis of KIAA1549-BRAF fused pLGGs. Upregulation in immune related pathways and Toll-Like Receptor (TLR) signaling was associated with lower risk. This study elucidates the synergistic dynamics between the biological processes that promote the risk of progression and radiomic-based risk-stratification signature. The proposed biomarker may be used to encourage targeted therapies in patients with increased predicted risk.
A novel endoscopic ultrasound-guided transluminal anchor device
Authors: Abhishek Agnihotri, Alexander Schlachterman
Journal: Endoscopy (2023)

Over the last decade, there has been significant advancement in the field of therapeutic endoscopic ultrasound (EUS) [1]. Multiple transluminal interventions are now performed, including the creation of gastrojejunostomies using a lumen-apposing metal stent (LAMS) and EUS-guided transgastric endoscopic retrograde cholangiopancreatography, among other examples [2]. These procedures carry risks of perforation, which occurs mostly because of stent misdeployment or migration [3]. Attempts to use a 19-gauge needle to place an anchor have been described previously [4] [5]; however, these attempts required manual loading of the anchor, making the procedure cumbersome. We report the use of a novel EUS-guided transluminal anchor and cinch (S-Lock).
SURG-06. ENHANCED DELIVERY OF ANTI-PD1 FOR TREATMENT OF DIFFUSE MIDLINE GLIOMA USING FOCUSED ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER OPENING
Authors: Danae Kokossis, Hong-Jian Wei, Matthew Gallitto, Nina Yoh, Nicholas McQuillan, Masih Tazhibi, Xander Berg, Xu Zhang, Luca Szalontay, Robyn D Gartrell, Jovana Pavisic, Zhiguo Zhang, Andrei Molotkov, Akiva Mintz, Elisa E Konofagou, Cheng-Chia Wu
Journal: Neuro-Oncology (2023)

Abstract Diffuse midline glioma with H3K27 mutation is a fatal central nervous system tumor, most commonly arising in the brainstem. Despite a multitude of clinical trials, prognosis remains poor with a median overall survival of 9-12 months. Immune-checkpoint inhibitors (ICIs) have transformed the treatment landscape of multiple solid tumors. Programmed cell death protein 1 (PD1) is an immune checkpoint protein expressed on the surface of activated T cells; interaction with its ligand, PDL1, is tumor-protective, dampening T cell response. Recent phase I clinical trials have shown that ICIs targeting proteins along the PD1/PDL1 axis are well tolerated in patients with DMG; however, efficacy remains low. The blood-brain barrier (BBB) poses a major challenge to the efficacious delivery of therapeutic agents with large molecular size, such as anti-PD1. Here we show that delivery of anti-PD1 can be enhanced over 3.5-fold using low intensity focused ultrasound (FUS) and concurrent microbubble administration to achieve reversible blood-brain barrier opening (BBBO) in a syngeneic mouse DMG model established with intracranial injection of cell line 4423 (PDGFB+, H3.3K27M, p53-/-). We measured this increased delivery of anti-PD1 after BBBO using Western Blot and 3D in vivo optical fluorescent imaging/CT (OI/CT) of Cy7 labeled anti-PD1. OI/CT revealed enhanced real-time antibody distribution peritumorally. Furthermore, we demonstrated that this combined treatment of FUS and anti-PD1 led to benefit in local control of tumor growth using volumetric analysis of MRI. Preliminary survival studies suggest a positive trend for overall survival. We consider these findings strong rationale for further investigation of the therapeutic effects of combinatorial treatment using FUS-mediated BBBO and ICIs for the treatment of DMG.
IMMU-20. EVALUATION OF B7-H3 NANOBODY CAR-T CELLS IN PEDIATRIC GLIOBLASTOMA
Authors: Mia Fanuzzi, Allison Cole, Mohit Pratap Singh, Dan Li, Ruixue Wang, Tianyuzhou Liang, Mitchell Ho, Anandani Nellan
Journal: Neuro-Oncology (2023)

Abstract Chimeric antigen receptor (CAR)-T cell therapies are an undoubted success in childhood acute lymphoblastic leukemia; however, this success has not translated clinically to any childhood solid tumor. B7-H3 has been found to be highly expressed in pediatric brain tumors and correlates with tumor progression and poor prognosis. We utilized a novel nanobody based CAR-T cell which can bind tumor antigens with high affinity. We hypothesize that anti-B7-H3 nanobody CAR-T cells mediate more potent antitumor effects both in vitro and in vivo compared to existing antibody-based B7-H3 CAR-T cells. High expression of B7-H3 was confirmed on the surface of two pediatric glioblastoma cell lines by flow cytometry and Quantibrite staining. B7-H3 nanobodies isolated from camel phage libraries were cloned into lentiviral CAR-T cell constructs. We manufactured CAR-T cells by lentiviral transduction of human T cells. Glioblastoma tumor cells were co-cultured with B7-H3 CAR-T cells vs. control T cells. We confirmed B7-H3 specific cytokine release by CAR-T cells via ELISA and effective tumor cell killing via two different cytotoxicity assays (impedance or luciferase based). Nanobody based B7-H3 CAR-T cells exhibited statistically significant higher cytokine release and cytotoxicity compared to antibody based B7-H3 CAR-T cells. In vivo studies are currently evaluating the efficacy of intracerebroventricular delivery of B7-H3 CAR-T cells against two orthotopic glioblastoma models utilizing multiple human donor T cells in immunocompromised mice. We are simultaneously developing a syngeneic orthotopic glioblastoma model to evaluate the nanobody based B7-H3 CAR-T cell cross-reactive in mice utilizing an immunocompetent model. Careful investigation of CAR-T cell therapy in appropriate immunocompetent in vivo models is needed to develop effective immunotherapy for clinical application.